HIV-1 infection can be complicated by renal disease of diverse pathology. HIV-associated nephropathy (HIVAN) is frequently characterized by proteinuria, focal glomerulosclerosis (FGS), and tubulointerstitial injury. The pathogenesis of HIVAN is unknown. HIV genetic material has been found in biopsy tissue of infected patients, suggesting direct infectivity of renal tissue. Mononuclear cell infiltration has also been observed in glomeruli and interstitium of HIV-infected patients, suggesting a role for infected monocytes in the development of HIVAN. In this proposal, it is hypothesized that HIV-1 infected mononuclear cells alter mesangial cell function, causing changes that can lead to mesangial expansion and FGS. To address this hypothesis, cultured human mesangial cells derived from both fetal and adult kidneys will be exposed to products of HIV-infected mononuclear cells, including cytokines, free HIV- 1, and viral-encoded proteins such as gp120 and Tat. The effects of these factors on mesangial cell proliferation, expression of type IV collagen and enzymes important in collagen degradation, and expression of cytokines will be determined. It is also hypothesized, and supported by preliminary data, that activated mesangial cells promote HIV-1 replication in infected mononuclear cells. Intraglomerular HIV-1 replication may be a fundamental mechanism of HIVAN. Neutralization experiments using specific antibodies will investigate whether cytokines produced by activated mesangial cells stimulate HIV-1 replication. Together, the above experiments will model possible mechanisms of glomerular "cross-talk" between mesangial cells and infiltrating HIV-infected mononuclear cells. Last, it is hypothesized that mesangial cells undergo HIV-1 infection. This might be responsible, in part, for the development of glomerulopathy in HIVAN. Experiments will examine the mechanism of mesangial cell HIV-1 infectivity and specifically address whether mesangial cell activation is necessary for HIV-1 infectivity. Experiments will also determine whether chronic exposure to free virus elicits mesangial cell infection or whether direct contact with HIV-infected mononuclear cells is necessary for mesangial cell infection. Importantly, because HIVAN is predominately a disease of African- Americans, in all experiments mesangial cells cultured from renal tissue of Caucasians and African-Americans will be compared. Collectively, the proposed experiments will provide important information regarding mechanisms by which HIV-1 infection can cause mesangial alterations which lead to glomerulopathy characteristic of HIVAN.